In December 2011, Hunt et al published a strong refutation of the role of rare functional variants in SIAE in autoimmune disease: http://www.nature.com/ng/journal/v44/n1/full/ng.1037.html

The previous study had found something like 24 "severe" variants in cases and only 2 in controls, and noted the variants were functional.

Now, one of the important takeaways is that functional variant is not necessarily a synonym for disease causing variant. However, another important question raised by the exchange is, what led to this false association, and could it have been prevented?

One of the potential confounds noted by Hunt et al in their study is that, although principal component analysis is effective at identifying population structure coarsely, fine population substructure might not be captured in a PCA.

So, with all this as context, I was hoping to ask, "has there been any development in methods of rooting out and eliminating confounds in rare variant studies?" and second "how could one go about finding fine substructure to which Hunt et al are alluding in ones data?"